Fluorene derivatives



United States Patent FLUORENE DERIVATIVES James F. Kerwin and Glenn E.Ullyot, Philadelphia, Pa.,

assignors to dmith, Kline & French Laboratories, Philadelphia, Pan, acorporation of Pennsylvania No Drawing. Application September 12, 1952,Serial No. 309,362

9 Claims. (Cl. 260--570.'7)

This invention relates to certain new chemical compounds which are ofvalue by virtue of the fact that they possess physiological propertiesand, further, possess utility as intermediates in the preparation ofcompounds possessing sympatholytic properties and which are disclosed inPatent 2,656,387. By sympatholytic properties where used herein in thespecification is meant the ability to block and/or reverse responsescaused by epinephrine, epinephrine like substances and othersympathomimetic amines.

The compounds according to this invention are, broadly speaking,fi-hydroxyethylamines in which the nitrogen is linked to fluorene in the9 position.

Broadly speaking, the new compounds in accordance with this inventionwill have the following structure:

in which:

Y is a member of the group consisting of alkyl groups of not in excessof 4 carbon atoms, phenyl, tolyl and anisyl;

n is an integer from the group consisting of 2 and 3; and

R is a member of the group consisting of hydrogen and methyl.

This invention also contemplates the salts of the above compounds formedwith inorganic acids, as, for example, sulfamic, hydrochloric,hydrobromic, sulfuric, phosphoric, nitric, etc., and with organic acids,as, for example, tartaric, oxalic, succinic, glycolic, comphorsulfonic,maleic, etc. More specifically, such salts may preferably be formed withorganic and inorganic acids which have an ionization constant of notless than l at 18 C.

Generally speaking, any of the compounds in accordance with thisinvention as defined by the above structural formula will be produced bythe preparation of a 9-(fihydroxyethylamino) fluorene by interacting9-bromofiuorene with an N-monosubstituted amino alcohol.

As more specifically illustrative of procedures generally applicable formaking the compounds included within the structural formula given above,9-bromofluorene and an amino alcohol are mixed and heated together untilreaction is complete. The use of an excess of amino alcohol is desirablein order to remove hydrogen bromide, which is formed as a lay-product ofthe reaction. If desired, a suitable solvent may be used, such asbenzene, alcohol, or the like. Again, instead of using an excess ofamino alcohol, the reaction may be carried out in the presence of analkaline reagent, such as sodium bicarbonate, a tertiary amine, such asdimethylaniline, diethylaniline, or the like.

On completion of the reaction, the product may be recovered bydistillation or by effecting the formation of a hydrohalide salt andrecrystallizing. The reaction will be made apparent by the following:

In the above formula illustrative of the reaction for 20 the productionof the compounds in accordance with this invention and hereinafter Y andR are as indicated in connection with the above structural formula forthe compounds according to this invention, it being obvious that for thepreparation of compounds in accordance with this invention theparticular amino alcohol for reaction with 9-bromofiuorene will beselected with consideration for the particular compound to be produced.

The compounds in accordance with this invention are useful for thepreparation of the free base and its organic and inorganic acid additionsalts, the free base having the following structure:

in which Y is a member of the group consisting of alkyl groups of not inexcess of 4 carbon atoms, phenyl, tolyl and anisyl; n is an integer fromthe group consisting of 2 and 3; R is a member of the group consistingof hydrogen and methyl; X is a member selected from the group consistingof chlorine, bromine and iodine. The co1npounds of the immediately abovestructural formula and its organic and inorganic acid addition saltshave syinpatholytic properties. The hydrochloride and hydrobromide saltsof the immediately above formula are exemplary of salts havingsympatholytic properties.

In using the compounds of this invention as intermediates to prepare thesympatholytic compounds of the immediately above structural formula andtheir salts, the

hydroxyl group will be replaced with a halogen group as chlorine,bromine or iodine by, for example, reacting the compounds of thisinvention with a thionyl halide or with a halogen acid in a well knownmanner. It is preferred to mix the selected compound of this inventionwith an equirnolar quantity of thionyl halide in solution in chloroformand then reflux for about 2 to 3 hours. The removal of the chloroformunder reduced pressure leaves the desired ,B-haloethylaminecorresponding to the selected starting compound of this invention.

For the preparation of 9-(fl-hydroxyethylamino) fluorenes in accordancewith this invention, a wide variety of amino alcohols may be used forreaction with 9-bromofluorene, many of which have been reported in theliterature and others of which, given their structure as above,

may be readily prepared by well known methods. Thus,

by way of example the following amino alcohols may be used:

N-('ymethoxypropyl) ethanolamine N- ,B-ethoxyethyl) ethanolamine N-8-butoxyethyl) ethanolamine N- fl-phenoxyethyl) ethanolamineN-(fl-phenoxyisopropyl) ethanolamine N- B-phenoxyisopropyl-1-amino-2-propanol N ,8- o-toloxy ethyl] ethanolamine N- E B-(p-anisyl) ethyl] ethanolamine As an alternative procedurefor thepreparation of compounds in accordance with this invention,9-bromofluorene may be reacted with ethanolamine or 1-arnin0-2- propanolin a solvent such as, for example, benzene or alcohol, preferably withan excess of the reacting amine. The N- (9-fiuorenyl)amino-ethanol orcorresponding propanol thus formed is then reacted with an alkoxyalltylhalide or aryloxyalkyl halide of the type YOCnI'IZnX, in which X is ahalogen, in an inert solvent such as toluene or xylene, in the presenceof an acid-binding agent which may comprise an excess of the reactingamine or other added agent such as potassium carbonate, sodiumbicarbonate, and the like. The reaction of the alternate procedure willbe made apparent by the following:

The following specific examples will be illustrative of compounds inaccordance with this invention and procedure for their preparation aswell as their utility as intermediates to make compounds having ahalogen substituted for the hydroxyl group and having sympatholyticproperties; and will serve, together with the foregoing, to makeapparent to those skilled in the art the preparation of all compounds inaccordance with this invention having the structure hereinbeforeindicated. The last formed product, a S-haloethylamine salt, of eachexample, has sympatholytic properties.

EXAMPLE 1 N-(v-merhoxypropyl)-N(9-fluorenyl)-,B- lzydroxyethylaminehydrochloride One mole of y-methoxypropyl chloride is added to threemoles of ethanolamine at 140-150" over a two hour period. Uponcompletion of the addition, heating is continued for another two hoursand the mixture is diluted with water and extracted with chloroform. Ondistillation of the chloroform solution N-( -methoxypropyl)ethanolamine, B. P. 9093/5 'mm. is obtained.

areaosv A solution of 20 g. of N-('y-methoxypropyDethanolamine and 18.4g. of 9-bromofiuorene dissolved in cc. of dry benzene is refluxed for 2hours. The solution is concentrated to approximately 60 cc. and theremainder refluxed for one hour. Ether is added to the cooled solutionand the solution is decanted from the hydrobromide oil, washed threetimes with water, and dried over potassium carbonate. The hydrochloridesalt is prepared and the solid tertiary aminoalcohol is crystallizedfrom alcohol-ether, M. P. 149.5-l51.5 C.

As illustrative of the use of this compound as an intermediate, forexample, for the preparation of N-(y-methoxypropyl -N- 9-fiuorenyl)-{3-chlorethylamine hydrochloride, a solution of 4.8 g. of thionylchloride in 10 cc. of chloroform is added slowly to a solution of 11 g.of the N 9-fiuorenyl) -N- -methoxypropyl) aminoethanol hydrochlorideprepared above in 50 cc. of chloroform, while the solution is cooled inan ice bath. The solution is then refluxed on a water bath for threehours. The solvent is removed under reduced pressure leaving an oilwhich solidifies when stirred with ether. The solid,N-(y-methoxypropyl)-N-(9-fluoreny1)-B-chlorethylamine hydrochloride iscollected and crystallized three times from alcoholether M. P. l469 C.

EXAMPLE 2 N ,B-ethoxyethyl -N (9-fluorenyl 43- hydroxyethylaminehydrochloride This will be prepared in the manner described for thepreparation of Example 1, using ethoxyethyl bromide as startingmaterial. By addition or" this halide to ethanolamine at 140, dilutionwih water and repeated extraction with ether,N-(fl-ethoxyethyl)ethanolamine is formed. Two molar equivalents of theamine are heated with one molar equivalent of 9-oromofiuorene in benzenesolution for two hours. The cooled mixture is diluted with ether andfiltered, and the filtrate treated with hydrogen chloride gas to obtainN-(fl-ethoxyethyD-N-(9- fluorenybethanolamine hydrochloride. Asillustrative of the use of this compound as an intermediate, forexample, for the preparation of N-(fi-ethoxyethyl)-N-(9-fiuorenyl)-,B-chloroethylamine hydrochloride, a solution of the salt in chloroformmay be refluxed with thionyl chloride to form the B-chloro product.

EXAMPLE 3 N-(B-butoxyethyl) -N- (9-fluorenyl) -fl-hydroxyethylaminehydrochloride This compound will be prepared in the manner described inthe preparation of Example 1. ,B-Butoxyethyl bromide is employed toalkylate ethanolamine and the resulting N-(B-butoxyethyl) ethanolamineis reacted with 9-bromofluorene. As illustrative of the use of thiscompound as an intermediate, for example, for the preparation ofN-(fi-butoxyethyl)-N-(9-fluorenyl)-fl-chlorethy1- amine hydrochloride,the hydroxyl group may be replaced, by means of thionyl chloride inchloroform solution, with chlorine to form the N-(B-butoxyethyl)-N-9-fiuorenyl)-p-chlorethylamine hydrochloride. I

EXAMPLE 4 A solution of g. of 9-bromofluorene and 14.8 g. ofN-(phenoxyethyl)aminoethanol dissolved in 40 cc. of dry benzene isrefluxed for 2 /2 hours. One hundred cc. of ether is added and themixture is filtered, washing the hydrobromide salt with ether. Dryhydrogen chloride is passed through the filtrate forming a solidcompound which is crystallized from alcohol, M. P. 169-1625 C.

As illustrative of the use of this compound as an intermecliate, forexample, for the preparation of N-(fiphenoxyethyl) N (9-fiuorenyl) ,Bchloroethylamine hydrochloride, a solution of 4.7 g. of thionyl chloridedissolved in 10 cc. of dry chloroform is added to a cooled suspension of10 g. of N-(9-fluorenyl)-N-(phenoxyethyl) aminoethanol hydrochloride(prepared above) in 80 cc. of dry chloroform. The solution is refluxedfor three hours. The chloroform is removed under reduced pressureleaving a solid residue which is crystallized twice from alcohol toyield a product with a M. P. of 167-9 C.

EXAMPLE 5 N-(fi-phenoxyisopropyl)-N-(9-flu0renyl) 8-hydroxyethylaminehydrochloride One mole of 1-phenoxy-Z-chloropropane, prepared froml-phenoxy-2-propanol and thionyl chloride, is added over a two hourinterval to three moles of boiling ethanolamine. The mixture is refluxedfor three hours, diluted with water, and extracted with ether. The ethersolution is then extracted with dilute acid, the acid extract made basicand the product taken up into ether. Removal of the ether leaves 1-(fl-phenoxyisopropyl)ethanolamine, which is recrystallized frompetroleum ether.

48 gms. of N-(fi-phenoxyisopropyl) ethanolamine is refluxed for sixhours with a solution of 30.8 gms. of 9- bromo-fiuorene in 150 ml. ofbenzene. The resulting solution is poured into water and the waterextract separated, this procedure being repeated twice, followed byboiling of the organic layer to eliminate the Water. The residue isdiluted with ether and dry hydrogen chloride is introduced into thesolution. The resulting oil which slowly crystallizes provides aprecipitate which is recrystallized from ethanol and ether to yield acolorless crystalline product melting at l68-9 C.

As illustrative of the use of this compound 'as an intermediate, forexample, for the preparation of N-(flphenoxyisopropyl) N (9-fluorenyl)5. chloroethylamine hydrochloride, a solution of 29.6 grns. of N-phenoxyisopropyl-N-(9-fluorenyl) aminoethanol hydrochloride and 10.7gms. thionyl chloride in 100 ml. of chloroform is warmed at 35 for /2hour and then refluxed for 2 /2 hours. Upon removal of the solvent underreduced pressure there remains an oily residue which is covered withether and allowed to stand overnight. The salt which solidifies isrecrystallized from alcohol and ether to provide a product which meltsat 150-1 C.

6 EXAMPLE 6 N-(B-phenoxyisopropyl) -N- (Q-fluorenyl) -1-amino-2-hydroxypropane hydrochloride H; CH3 1-phenoxy-2-chloropropane is added toboiling l-amino- 2-propanol and the mixture is refluxed .for three hoursto prepare the N-(,8-phenoxyisopropyl)-l-amino-2- propanol in a manneridentical with that described in Example 5.

The 9-fluorenyl group is introduced into the molecule by refluxing asolution of 2 molar equivalents ofN-(flphenoxyisopropyl)-1-amino-2-propanol with one molar equivalent of9-bromoflu0rene in benzene solution. The hydrobromide salt of thestarting amino alcohol is filtered off andhydrogen chloride gas isintroduced into the filtrate to obtain N-(fl-phenoxyisopropyl) N(9-fluorenyl)-1- amino-Z-propanol hydrochloride. This salt may be thenrefluxed with thionyl chloride in chloroform solution to formthecorresponding fl-chloro product.

EXAMPLE 7 N [,B-( o-toloxy ethyl] N -(9-fluorenyl -,8-hydroxyethylaminehydrochloride A solution of one mole of N-[fi-(o-toloxy)ethyl]ethanolamine and one-half mole of 9-bromofluorene in 750 cc. of benzeneis refluxed for 2%. hours as in Example 4. The mixture is diluted withether, filtered and the filtrate is treated with hydrogen chloride ga toform the N- [,8- (o-toloxy) ethyl] -N (9 fluorenyl) ethanolaminehydrochloride. This salt and an equimolar quantity of thionyl chloridemay be heated in refluxing chloroform solution to form thefl-chlorethylamine hydrochloride product.

EXAMPLE 8 N ,B-phenoxyethyl -N (9-fluorenyl -fihydroxyethylamz'nehydrobromide A solutionof 10 g. of 9-brornofluorene and 14.8 g. ofN-(phenoxyethyl)aminoethanol dissolved in 40 cc. of dry benzene isrefluxed for 2 /2 hours. One hundred cc. of ether is added and themixture is filtered, washing the hydrobromide salt with ether. Dryhydrogen bromide is passed through the filtrate forming a solid compoundwhich is crystallized from alcohol.

As illustrative of the use of this compound as an intermediate, forexample, for the preparation of N-(flphenoxyethyl -N- 9-fluorenyl)-p-bromethylamine hydrobromide, the above prepared salt and an equimolarquantity of thionyl bromide are heated in refluxing chloroform solution,refluxing is carried out for two hours and the chloroform removed underreduced pressure leaving a solid residue which is crystallized twicefrom alcohol to yield the desired fi-bromethylamine hydrobromide.

7 EXAMPLE 9 Using N-[fl-(p-anisyloxy)ethyllethanolamine as startingmaterial, the procedure of Example 4 will be followed to form thiscompound. The corresponding ,B-chloro product may be formed by reactionwith thionyl chloride.

In the foregoing examples hydrochlorides according to this invention areexemplified. However, it will be understood and readily appreciated bythose skilled in the art that the foregoing examples will illustrateorganic or inorganic salts generally and will serve as specific examplesof those organic and inorganic salts heretofore mentioned specificallyby the substitution in the several foregoing illustrative structures ofany of the acid groups heretofore specifically mentioned or the acidgroup of any other desired organic or inorganic acid for the HCl in theseveral foregoing examples, respectively.

The foregoing examples illustrate the salts contemplated by thisinvention. The bases contemplated by this invention according to thebroad and more particular structural formulae herein disclosed arespecifically exemplified as will be obvious to anyone skilled in the artby reference to the foregoing specific examples with the removal fromthe structure illustrated thereby of the acid group, i. e.,

I-ICl.

The bases contemplated by this invention will be formed by interactingthe salts contemplated by this invention and herein exhaustivelyexemplified with one molecular equivalent of a strong alkali such, forexample, as sodium hydroxide, potassium hydroxide, lithium hydroxide, orthe like, in aqueous solution say, for example, a l%40% solution. a

The compounds contemplated by this invention will be variously opticallyinactive or optically active and it will be understood that theoptically inactive and optically active forms of thecompoundscontemplated by this invention are all included Within thescope of this invention.

The various types of compounds having the structure embodying thisinvention as illustrated by the above specific examples and examples ofthe various types of compounds will be readily prepared by the generalmethod of preparation described above as amplified by the description ofpreparation of the several specific examples. The starting material forthe preparation of any given compound Within the structure contemplatedby this invention will be found among known compounds, or, its structurebeing obvious With reference to any particular compound desired to beprepared, will be readily prepared by known methods.

This application is a continuation in part of our application Serial No.198,484, filed November 30, 1950 which is a continuation in part of ourapplication Serial No. 37,494, filed July 7, 1948, both now abandoned.

What is claimed is:

l. A compound of the class consisting of a free base and its acidaddition salts, the free base having the formula:

in which Y is a member of the group consisting of alkyl groups of not inexcess of 4 carbon atoms, phenyl, tolyl and anisyl; n is an integer fromthe group consistlng of 8 2 and 3; R is a member of the group consistingof hydrogen and methyl.

2. The acid addition salts of a compound having the structure 3. Theacid addition salts of a compound having the structure 4. The acidaddition salts of a compound having the structure cH -OCH2CHl l-CH OHgOH5. A compound having the structure CHa-OCH2OHzCH2NCH2-CH2OH-HO1 6. Acompound having the structure 7. A compound having the structure 8. Acompound having the structure CsHs-OCH CH NCH2OHzOH-HC1 9. A compoundhaving the structure CH3 References Cited in the file of this patentUNITED STATES PATENTS 2,573,607 Rieverschl Oct. 30, 1951 2,656,387Kerwin et a1. Oct. 20, 1953 FOREIGN PATENTS 675,243 Great Britain July9, 1952 675,326 Great Britain July 9, 1952

1. A COMPOUND OF THE CLASS CONSISTING OF A FREE BASE AND ITS ACIDADDITION SALTS, THE FREE BASE HAVING THE FORMULA: